Cyclic ADP-ribose (cADPR) is a naturally occurring cyclic nucleotide and a potent mediator of calcium mobilization in many mammalian tissues. It is biosynthesized from NAD+ by ADP-ribosyl cyclases in a variety of mammalian and invertebrate tissues. In our previous work, we have completed the structural assignment of cyclic ADPR by correlating cADPR to N(-(5(-phosphoribosyl)AMP and developed the first nonenzymatic stereoselective synthesis of cADPR from NAD+. In order to get more data concerning the generality of our chemical cyclization procedure and the specificity of the ADP-ribosyl cyclase from Aplysia californica, we recently have synthesized a series of novel derivatives of cADPR with the chemical and enzymatic cyclization of the corresponding NAD analogs. The availability of these compounds will allow us to examine their ability to induce or inhibit Ca2+ release in biological systems as well as to establish relationship between chemical structure and biological activity. This knowledge will in turn aid us in the design and synthesis of compounds for affinity labeling of the ryanodine receptor and the preparation of affinity ligands for isolation of cADPR receptor(s).